Osteopetrosis includes a group of inherited diseases in which inadequate bone resorption is caused by osteoclast dysfunction. Although molecular defects have been described for many animal models of osteopetrosis, the gene responsible for most cases of the severe human form of the disease (infantile malignant osteopetrosis) is known. Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life. Osteoclasts are present in normal or elevated numbers in individuals affected by autosomal recessive osteopetrosis, suggesting that the defect is not in osteoclast differentiation, but in a gene involved in the functional capacity of mature osteoclasts. Some of the mouse mutants have a decreased number of osteoclasts, which suggests that the defect directly interferes with osteoclasts differentiation. In other mutants, it is the function of the osteoclasts that seems to be affected, as they show normal or elevated numbers of non-functioning osteoclasts. Here we show that TCIRG1, encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, is mutated in five of nine patients with a diagnosis of infantile malignant osteopetrosis. Our data indicate that mutations in TCIRG1 are a frequent cause of autosomal recessive osteopetrosis in humans.
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We thank R. Dulbecco, L. Rossi Bernardi and D. Brown for their encouragement; M. Perrella for comments; S. Sencer and D. Unruh for assistance with samples from family members; V. Starnes for typing of the manuscript; and D. Strina, L. Susani, M. Littardi, J. Hatton and E.M. Catò for technical assistance. This work was partially supported by grants from Telethon, Italy (E.917 to A.V.; E.C0682 to A.F. and E.668 to L.D.N.), Biomed2 grant CT-983007 (to L.D.N.) and the Minnesota Medical Foundation and Vikings Children Fund (P.J.O.).